Pharmacophoric Requirements for the Cannabinoid Side Chain. Probing the
Cannabinoid Receptor Subsite at C1‘

Earlier work from our laboratories has provided evidence for the existence of a subsite within
the CB1 and CB2 cannabinoid receptor binding domain corresponding to substituents at the
benzylic side chain position of classical cannabinoids. The existence and stereochemical features
of this subsite have now been probed through the synthesis of a novel series of (−)-Δ<sup>8</sup>-tetrahydrocannabinol analogues bearing C1‘-ring substituents. Of the compounds described
here, those with C1‘-dithiolane (<b>1c</b>), C1‘-dioxolane (<b>2d</b>), and cyclopentyl (<b>2a</b>) substituents
exhibited the highest affinities for CB1 and CB2. We used molecular modeling approaches to
better define the stereochemical limits of the putative subsite. In vitro pharmacological testing
found <b>1c</b> to be a potent CB1 agonist.